EP2487153A1 - Substituierte Cyclopentane mit Prostaglandinwirkung - Google Patents

Substituierte Cyclopentane mit Prostaglandinwirkung Download PDF

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Publication number
EP2487153A1
EP2487153A1 EP12167472A EP12167472A EP2487153A1 EP 2487153 A1 EP2487153 A1 EP 2487153A1 EP 12167472 A EP12167472 A EP 12167472A EP 12167472 A EP12167472 A EP 12167472A EP 2487153 A1 EP2487153 A1 EP 2487153A1
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EP
European Patent Office
Prior art keywords
compound
alkyl
mmol
formula
represented
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP12167472A
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English (en)
French (fr)
Inventor
Robert M. Burk
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Allergan Inc
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Allergan Inc
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Publication of EP2487153A1 publication Critical patent/EP2487153A1/de
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups

Definitions

  • Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy ocular hypertensive episodes, glaucoma, and as presurgical adjuncts.
  • Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract. Glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision.
  • the underlying causes of primary glaucoma are not yet known.
  • the increased intraocular tension is due to the obstruction of aqueous humor outflow.
  • chronic open-angle glaucoma the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded.
  • acute or chronic angle-closure glaucoma the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of the iris forward against the angle, and may produce pupilary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity.
  • Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm.
  • Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe, and may plug the drainage channel with exudates.
  • Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
  • prostaglandins and prostamides have recently become the first line treatments of glaucoma.
  • Certain eicosanoids and their derivatives are currently commercially available for use in glaucoma management.
  • Eicosanoids and derivatives include numerous biologically important compounds such as prostaglandins and their derivatives.
  • Prostaglandins can be described as derivatives of prostanoic acid which have the following structural formula:
  • prostaglandins are known, depending on the structure and substituents carried on the alicyclic ring of the prostanoic acid skeleton. Further classification is based on the number of unsaturated bonds in the side chain indicated by numerical subscripts after the generic type of prostaglandin [e.g. prostaglandin E 1 (PGE 1 ), prostaglandin E 2 (PGE 2 )], and on the configuration of the substituents on the alicyclic ring indicated by ⁇ or ⁇ [e.g. prostaglandin F 2 ⁇ (PGF 2 ⁇ )].
  • PGE 1 prostaglandin E 1
  • PGE 2 prostaglandin E 2
  • PPF 2 ⁇ prostaglandin F 2 ⁇
  • Y has from 0 to 14 carbon atoms and is: an organic acid functional group, or an amide or ester thereof; hydroxymethyl or an ether thereof; or a tetrazolyl functional group;
  • Z is halo, -OH, -OR, -SH, -CF 3 , or -CN; each R 1 is independently O, S, CH 2 , or if R 1 forms a double bond to another R 1 , then both are CH, provided that O-O, S-O, and O-S are not present, and each R is independently -H, C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 1-6 acyl.
  • These compounds are useful for reducing intraocular pressure. Reduction of intraocular pressure has been shown to delay or prevent the onset of primary open angle glaucoma, and to delay or prevent further vision loss in patients with primary open angle glaucoma. Thus, these compounds are also useful for treating glaucoma. These compounds are also useful for growing hair, including one or more of: increasing the number of individual hairs, increasing the length of individual hairs, and increasing the width or thickness of individual hairs. These compounds are also useful for improving the appearance of hair, including increasing its gloss, shine, or other properties related to the reflection or dispersion of light, as well as changing the color of hair, including changing hair from grey or white to the color the hair was before it turned grey or white, such as red, brown, or black.
  • the compound could be dissolved or suspended in an aqueous solution or emulsion that is buffered to an appropriate pH, and administered topically to an eye of a mammal (see US 7,091,231 ).
  • treat refers to the use of a compound, composition, therapeutically active agent, or drug in the diagnosis, cure, mitigation, treatment, or prevention of disease or other undesirable condition.
  • reference to a compound should be construed broadly to include compounds, pharmaceutically acceptable salts, prodrugs, tautomers, alternate solid forms, non-covalent complexes, and combinations thereof, of a chemical entity of a depicted structure or chemical name.
  • a pharmaceutically acceptable salt is any salt of the parent compound that is suitable for administration to an animal or human.
  • a pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt.
  • a salt comprises one or more ionic forms of the compound, such as a conjugate acid or base, associated with one or more corresponding counter-ions. Salts can form from or incorporate one or more deprotonated acidic groups (e.g. carboxylic acids), one or more protonated basic groups (e.g. amines), or both (e.g. zwitterions).
  • a prodrug is a compound which is converted to a therapeutically active compound after administration. For example, conversion may occur by hydrolysis of an ester group or some other biologically labile group.
  • Prodrug preparation is well known in the art. For example, " Prodrugs and Drug Delivery Systems," which is a chapter in Richard B. Silverman, Organic Chemistry of Drug Design and Drug Action, 2d Ed., Elsevier Academic Press: Amsterdam, 2004, pp. 496-557 , provides further detail on the subject. In particular, alkyl esters having such as methyl, ethyl, isopropyl, and the like are contemplated. Also contemplated are prodrugs containing a polar group such as hydroxyl or morpholine. Examples of such prodrugs include compounds containing the moieties -CO 2 (CH 2 ) 2 OH, and the like.
  • Tautomers are isomers that are in rapid equilibrium with one another.
  • tautomers may be related by transfer of a proton, hydrogen atom, or hydride ion.
  • Alternate solid forms are different solid forms than those that may result from practicing the procedures described herein.
  • alternate solid forms may be polymorphs, different kinds of amorphous solid forms, glasses, and the like.
  • Non-covalent complexes are complexes that may form between the compound and one or more additional chemical species that do not involve a covalent bonding interaction between the compound and the additional chemical species. They may or may not have a specific ratio between the compound and the additional chemical species. Examples might include solvates, hydrates, charge transfer complexes, and the like.
  • a dashed line represents the presence or absence of a bond.
  • Y is an organic acid functional group, or an amide or ester thereof; or Y is hydroxymethyl or an ether thereof; or Y is a tetrazolyl functional group.
  • Y is limited to from 0 to 14 carbon atoms, from 0 to 5 oxygen atoms, from 0 to 2 nitrogen atoms, from 0 to 2 sulfur atoms, from 0 to 1 phosphorous, and any necessary hydrogen atoms.
  • organic acid functional group is an acidic functional group on an organic molecule. While not intending to be limiting, organic acid functional groups may comprise an oxide of carbon, sulfur, or phosphorous. Thus, while not intending to limit the scope of the invention in any way, in certain compounds Y is a carboxylic acid, sulfonic acid, or phosphonic acid functional group.
  • Esters and amides of organic acid functional groups contain have a nitrogen or an oxygen atom directly attached to the acidic core atom, where the oxygen atom is not part of an -OH moiety.
  • the acidic core atom is the atom that is bonded to -OH or -SH in the organic acid functional group.
  • esters of amides of carboxylic acids, sulfonic acid, and phosphonic acid functional groups are depicted below.
  • An amide may also have an -SO 2 - moiety.
  • the amide - CONHSO 2 R 3 wherein R 3 is a hydrocarbyl of from 1 to 14 carbon atoms, is contemplated.
  • R, R 1 , R 2 , and R 3 are hydrocarbyl subject to the constraint that Y may not have more than 14 carbon atoms.
  • Hydrocarbyl is a moiety consisting of carbon and hydrogen, including, but not limited to:
  • C 1-6 hydrocarbyl is hydrocarbyl having 1, 2, 3, 4, 5, or 6 carbon atoms.
  • C 1-6 alkyl is alkyl having 1, 2, 3, 4, 5, or 6, carbon atoms such as methyl, ethyl, propyl isomers, butyl isomers, pentyl isomer, and hexyl isomers, etc.
  • An unsubstituted tetrazolyl functional group has two tautomeric forms, which can rapidly interconvert in aqueous or biological media, and are thus equivalent to one another. These tautomers are shown below.
  • R 2 is C 1 -C 6 alkyl, phenyl, or biphenyl
  • other isomeric forms of the tetrazolyl functional group such as the one shown below are also possible, unsubstituted and hydrocarbyl substituted tetrazolyl up to C 14 are considered to be within the scope of the term "tetrazolyl.”
  • Y is -CO 2 R 4 , -CONR 5 R 6 , -CON(CH 2 CH 2 OH) 2 , - CONH(CH 2 CH 2 OH), -CH 2 OH, -P(O)(OH) 2 , -CONHSO 2 R 4 , -SO 2 NR 5 R 6 , wherein R 4 , R 5 and R 6 are independently H, C 1 -C 6 alkyl, C 1-6 hydroxyalkyl, unsubstituted phenyl, or unsubstituted biphenyl, provided that Y has no more than 14 carbon atoms.
  • Alk alkyl
  • Z is halo, -OH, -OR, -SH, -CF 3 , or -CN.
  • Each R 1 is independently O, S, CH 2 , or if R 1 forms a double bond to another R 1 , then both are CH, provided that O-O, S-O, and O-S are not present.
  • the chain formed by the R 1 groups may be one of those shown below.
  • Each R is independently -H, C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 1-6 acyl.
  • Hydroxyalkyl is alkyl having a hydroxyl attached. The hydroxyl could be attached at any position. C 1-6 hydroxyalkyl has from 1 to 6 carbon atoms.
  • Acyl is wherein Rx is hydrocarbyl.
  • C 1-6 acyl has from 1 to 6 carbon atoms.
  • X is Cl
  • Z is OH
  • Z is OH
  • Another embodiment is a compound represented by the formula wherein R 10 is H or C 1-6 alkyl.
  • Another embodiment is a compound represented by the formula wherein a dashed line represents the presence or absence of a bond, and Y is CO 2 (CH 2 ) 2 OH or
  • Another embodiment is method of reducing intraocular pressure comprising administering a compound disclosed herein to a mammal in need thereof.
  • Another embodiment is a method of treating glaucoma or ocular hypertension comprising administering a compound disclosed herein to a mammal in need thereof.
  • Another embodiment is a method of growing hair or improving the appearance of hair comprising administering a compound disclosed herein to a mammal in need thereof.
  • Another embodiment is use of a compound disclosed herein in the manufacture of a medicament for the treatment of glaucoma or ocular hypertension.
  • Another embodiment is use of a compound disclosed herein in the manufacture of a medicament for growing hair or improving the appearance of hair.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Ophthalmology & Optometry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP12167472A 2008-02-05 2009-02-03 Substituierte Cyclopentane mit Prostaglandinwirkung Withdrawn EP2487153A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US2617908P 2008-02-05 2008-02-05
US12/363,996 US8455547B2 (en) 2008-02-05 2009-02-02 Substituted cyclopentanes having prostaglandin activity
EP09708693A EP2245005A1 (de) 2008-02-05 2009-02-03 Substituierte cyclopentane mit prostaglandinwirkung

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
EP09708693.8 Division 2009-02-03

Publications (1)

Publication Number Publication Date
EP2487153A1 true EP2487153A1 (de) 2012-08-15

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EP12167472A Withdrawn EP2487153A1 (de) 2008-02-05 2009-02-03 Substituierte Cyclopentane mit Prostaglandinwirkung
EP09708693A Withdrawn EP2245005A1 (de) 2008-02-05 2009-02-03 Substituierte cyclopentane mit prostaglandinwirkung

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP09708693A Withdrawn EP2245005A1 (de) 2008-02-05 2009-02-03 Substituierte cyclopentane mit prostaglandinwirkung

Country Status (12)

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US (1) US8455547B2 (de)
EP (2) EP2487153A1 (de)
JP (1) JP5566912B2 (de)
KR (1) KR20100119787A (de)
CN (1) CN101959854A (de)
AU (1) AU2009212570B2 (de)
BR (1) BRPI0907913A2 (de)
CA (1) CA2713958A1 (de)
IL (1) IL207354A0 (de)
MX (1) MX2010008589A (de)
RU (1) RU2505530C2 (de)
WO (1) WO2009100057A1 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9315486B2 (en) 2013-10-29 2016-04-19 Allergan, Inc. Therapeutic cyclopentanols, compositions thereof, and methods for use thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0116358A1 (de) * 1983-02-12 1984-08-22 Bayer Ag Komplexe von Prostaglandinen
WO1998033497A1 (en) * 1997-02-04 1998-08-06 Johnstone Murray A Method of enhancing hair growth
WO2001074313A2 (en) * 2000-03-31 2001-10-11 The Procter & Gamble Company Compositions and methods for treating hair loss using c16 - c20 aromatic tetrahydro prostaglandins
WO2005013928A1 (en) * 2003-08-12 2005-02-17 Sucampo Ag Composition and method for promoting hair growth
US20050070516A1 (en) * 1997-10-28 2005-03-31 Vivus Inc. As-needed administration of an androgenic agent to enhance female desire and responsiveness
WO2006063179A1 (en) * 2004-12-10 2006-06-15 Allergan, Inc. 12-aryl prostaglandin analogs
WO2007060453A1 (en) * 2005-11-26 2007-05-31 Medical Research Council Promoting wound healing by administering a prostaglandin e and granulocyte-macrophage colony stimulating factor

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1388443A (en) * 1971-06-11 1975-03-26 Searle & Co Selective reduction of 9,15-dioxoprostanoic acids
JPS55133354A (en) * 1979-04-02 1980-10-17 Upjohn Co Prostaglandin derivatives
US4259516A (en) * 1979-04-02 1981-03-31 The Upjohn Company 19-Hydroxy-inter-oxa-13,14-dihydro-PG1 compounds
DE3304864A1 (de) * 1983-02-12 1984-08-16 Bayer Ag, 5090 Leverkusen Adsorbate von prostaglandinen
SE9702681D0 (sv) * 1997-07-10 1997-07-10 Pharmacia & Upjohn Ab Method and composition for treatment of impotence
US5877211A (en) * 1997-11-21 1999-03-02 Allergan EP2 receptor agonists as neuroprotective agents for the eye
US6410591B1 (en) * 2001-05-08 2002-06-25 Allergan Sales, Inc. 3,7 or 3 and 7 thia or oxa prostanoic acid derivatives as agents for lowering intraocular pressure
AU2004211936B2 (en) * 2003-02-11 2008-09-11 Allergan, Inc. 10,10-dialkyl prostanoic acid derivatives as agents for lowering intraocular pressure
DK1759702T3 (da) 2004-05-26 2009-04-20 Bayardo Arturo Jimenez Fremgangsmåde til fremstilling af en latanoprost-öjenoplösning og en således fremstillet oplösning
US7476755B2 (en) * 2006-05-04 2009-01-13 Allergan, Inc. Therapeutic compounds
US9254293B2 (en) 2006-06-16 2016-02-09 The Trustees Of The University Of Pennsylvania Methods and compositions for inhibiting or reducing hair loss, acne, rosacea, prostate cancer, and BPH

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0116358A1 (de) * 1983-02-12 1984-08-22 Bayer Ag Komplexe von Prostaglandinen
WO1998033497A1 (en) * 1997-02-04 1998-08-06 Johnstone Murray A Method of enhancing hair growth
US20050070516A1 (en) * 1997-10-28 2005-03-31 Vivus Inc. As-needed administration of an androgenic agent to enhance female desire and responsiveness
WO2001074313A2 (en) * 2000-03-31 2001-10-11 The Procter & Gamble Company Compositions and methods for treating hair loss using c16 - c20 aromatic tetrahydro prostaglandins
WO2005013928A1 (en) * 2003-08-12 2005-02-17 Sucampo Ag Composition and method for promoting hair growth
WO2006063179A1 (en) * 2004-12-10 2006-06-15 Allergan, Inc. 12-aryl prostaglandin analogs
US7091231B2 (en) 2004-12-10 2006-08-15 Allergan, Inc. 12-Aryl prostaglandin analogs
WO2007060453A1 (en) * 2005-11-26 2007-05-31 Medical Research Council Promoting wound healing by administering a prostaglandin e and granulocyte-macrophage colony stimulating factor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RICHARD B. SILVERMAN: "Organic Chemistry of Drug Design and Drug Action", 2004, ELSEVIER ACADEMIC PRESS, article "Prodrugs and Drug Delivery Systems", pages: 496 - 557

Also Published As

Publication number Publication date
JP5566912B2 (ja) 2014-08-06
JP2011511081A (ja) 2011-04-07
WO2009100057A1 (en) 2009-08-13
MX2010008589A (es) 2010-08-23
EP2245005A1 (de) 2010-11-03
AU2009212570B2 (en) 2014-04-10
AU2009212570A1 (en) 2009-08-13
KR20100119787A (ko) 2010-11-10
CN101959854A (zh) 2011-01-26
IL207354A0 (en) 2010-12-30
RU2010135795A (ru) 2012-03-20
CA2713958A1 (en) 2009-08-13
BRPI0907913A2 (pt) 2015-07-28
US20090197962A1 (en) 2009-08-06
US8455547B2 (en) 2013-06-04
RU2505530C2 (ru) 2014-01-27

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